Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-κB–mediated mechanism

Abstract

Loss of muscle mass, or sarcopenia, is nearly universal in cirrhosis and adversely affects patient outcome. The underlying cross-talk between the liver and skeletal muscle mediating sarcopenia is not well understood. Hyperammonemia is a consistent abnormality in cirrhosis due to impaired hepatic detoxification to urea. We observed elevated levels of ammonia in both plasma samples and skeletal muscle biopsies from cirrhotic patients compared with healthy controls. Furthermore, skeletal muscle from cirrhotics had increased expression of myostatin, a known inhibitor of skeletal muscle accretion and growth. In vivo studies in mice showed that hyperammonemia reduced muscle mass and strength and increased myostatin expression in wild-type compared with postdevelopmental myostatin knockout mice. We postulated that hyperammonemia is an underlying link between hepatic dysfunction in cirrhosis and skeletal muscle loss. Therefore, murine C2C12 myotubes were treated with ammonium acetate resulting in intracellular concentrations similar to those in cirrhotic muscle. In this system, we demonstrate that hyperammonemia stimulated myostatin expression in a NF-κB-dependent manner. This finding was also observed in primary murine muscle cell cultures. Hyperammonemia triggered activation of IκB kinase, NF-κB nuclear translocation, binding of the NF-κB p65 subunit to specific sites within the myostatin promoter, and stimulation of myostatin gene transcription. Pharmacologic inhibition or gene silencing of NF-κB abolished myostatin up-regulation under conditions of hyperammonemia. Our work provides unique insights into hyperammonemia-induced myostatin expression and suggests a mechanism by which sarcopenia develops in cirrhotic patients.signaling | portosystemic shunting

Pivotal role of glutamine synthetase in ammonia detoxification

“…The muscle-to-fat volume ratio also decreased in GS-KO/M mice but to a lesser extent (not shown). In agreement, expression of myostatin, which induces muscle loss, (13) had increased 1.4-fold in GS-KO/L muscle (Fig. 1C).…”

“…Another novel finding is that chronic GS deficiency, in particular that in liver, decreases whole-body muscle-to-fat ratio and increases myostatin expression in muscle, as in cirrhosis of the liver and hyperammonemia. (13) A recent study of similar liver-specific GS-deficient mice (15) showed that mild but chronic hyperammonemia also causes cerebral oxidative stress and behavioral changes. Although both studies observed a similar 2-fold increase in blood ammonia concentration in mice with a hepatic GS deficiency, they differed in basal blood ammonia concentration, which was >5-fold higher in the C57Bl6 mice that Qvartskhava et al (15) used than in the FVB mice we used.…”

“…The relation between glutamine-bound ammonia disposal as urea and glutamine production was investigated with [5][6][7][8][9][10][11][12][13][14][15] N-L-glutamine ("glutamine11") and 18 O-, 13 C-urea ("urea13"). Steady-state blood concentrations of glutamine11 were attained after 30 minutes and those of urea13 after 90 minutes.…”

Sarcopenia and Sarcopenic Obesity Are Prognostic Factors for Overall Survival in Patients with Cirrhosis

“…The present longitudinal study also supports this, as shown in the results, which indicate that the stage preceding sarcopenia is mainly a normal body composition, and the stage preceding sarcopenic obesity is mainly visceral obesity. Although the causes for this and the suppression of secondary sarcopenia that accompanies cirrhosis are unknown (17), at the present time, nutritional therapy, such as high-protein meals that are intended to maintain albumin, the administration of BCAA formulations, and the night-time administration of light meals, is suggested to be helpful (18,19).…”

Importance of sarcopenia parameter changes after living donor liver transplantation

“…These data are in line with results of a study by Tsien et al of 53 deceased brain donor liver transplantation (DDLT) recipients; of these, only 2 of 33 patients with sarcopenia pre-DDLT (defined on the basis of the sum of the psoas, para-spinal and abdominal wall muscles to L4 muscles obtained by CT) had a post-DDLT recovery, while 75% (15 patients) of the non-sarcopenic patients developed this condition pre-DDLT (13), possibly due to a post-DDLT upregulation of myostatin, a potent mediator of muscle depletion, high levels of which seem to be linked to hyperammonemia in patients with ESLD (14).…”